Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first part of this report on the Australian Health and Medical Research Congress, held November 25-29, 2002, in Melbourne, Australia, considers some of the symposia and three plenary lectures: Neurosteroids: Nature's Valium, G-Protein-Coupled Receptors and the Mike Rand Memorial Lecture. In the new era in relaxin research symposium, we learned that relaxin is a general antifibrotic agent rather than just a hormone of pregnancy. The drugs discussed in the drug discovery symposium included drugs from natural products, allosteric modulators, antibodies to cytokines and AM-336, an N-type Ca(2+) channel blocker. In the matrix proteases symposium, we learned of the importance of these enzymes in bone, endometrial remodeling and cardiovascular disease. The emphasis of the cytokine antagonist symposium was the involvement of cytokines in rheumatoid arthritis and how these effects could be inhibited with cytokine antagonists. The second part of this report is on the cardiovascular components of the meeting. One of the major strengths of Australian research is the cardiovascular area. Thus, it was not surprising that there were three major symposia with a cardiovascular theme this congress. Although the clinical trials of the NHE1 inhibitors in ischemia and reperfusion have been disappointing to date, evidence was presented in the sodium-hydrogen exchanger symposium that these agents might be beneficial in hypertrophy and heart failure. The discussion in the vessel wall biology in diabetes symposium ranged from molecular aspects to clinical trials. In this, and the NAD(P)H oxidases symposium, many new potential drug targets were discussed. The plenary lecture of the High Blood Pressure Research Council concerned the pathophysiology and management of obesity hypertension, and included a discussion of the drugs for weight reduction.
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PMID:Health and medical research down under in 2002. 1294 54

The discovery of the obesity gene and its product, leptin, it is now possible to examine the relationship between body fat and the neuroendocrine axis. A minimum percentage of body fat may be linked to onset of puberty and weaning-to-estrus interval in the pig. Adipose tissue is no longer considered as only a depot to store excess energy in the form of fat. Recent findings demonstrate that numerous genes, i.e., relaxin, interleukins and other cytokines and biologically active substances such as leptin, insulin-like growth factor-I (IGF-I), IGF-II and Agouti protein are produced by porcine adipose tissue, which could have a profound effect on appetite and the reproductive axis. Hypothalamic neurons are transsynaptically connected to porcine adipose tissue and may regulate adipose tissue function. In the pig nutritional signals such as leptin are detected by the central nervous system (CNS) and translated by the neuroendocrine system into signals, which regulate appetite, hypothalamic gonadotropin-releasing hormone (GnRH) release and subsequent luteinizing hormone (LH) secretion. Furthermore, leptin directly affects LH secretion from the pituitary gland independent of CNS input. Changes in body weight or nutritional status are characterized by altered adipocyte function a reduction in adipose tissue leptin expression, serum leptin concentrations and a concurrent decrease in LH secretion. During pubertal development serum leptin levels, hypothalamic leptin receptor mRNA and estrogen-induced leptin gene expression in fat increased with age and adiposity in the pig and this occurred at the time of expected puberty. In the lactating sow serum and milk leptin concentrations were positively correlated with backfat thickness and level of dietary energy fed during gestation as well as feed consumption. Although, these results identify leptin as a putative signal that links metabolic status and neuroendocrine control of reproduction, other adipocyte protein products may play an important role in regulating the reproductive axis in the pig.
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PMID:Leptin: a metabolic signal affecting central regulation of reproduction in the pig. 1592 73

The relaxin family peptides, although structurally closely related to insulin, act on a group of four G protein-coupled receptors now known as Relaxin Family Peptide (RXFP) Receptors. The leucine-rich repeat containing RXFP1 and RXFP2 and the small peptide-like RXFP3 and RXFP4 are the physiological targets for relaxin, insulin-like (INSL) peptide 3, relaxin-3 and INSL5, respectively. RXFP1 and RXFP2 have at least two binding sites--a high-affinity site in the leucine-rich repeat region of the ectodomain and a lower-affinity site in an exoloop of the transmembrane region. Although they respond to peptides that are structurally similar, RXFP3 and RXFP4 demonstrate distinct binding properties with relaxin-3 being the only peptide that can recognize these receptors in addition to RXFP1. Activation of RXFP1 or RXFP2 causes increased cAMP and the initial response for both receptors is the resultant of Gs-mediated activation and G(oB)-mediated inhibition of adenylate cyclase. With RXFP1, an additional delayed increase in cAMP involves betagamma subunits released from G(i3). In contrast, RXFP3 and RXFP4 inhibit adenylate cyclase and RXFP3 causes ERK1/2 phosphorylation. Drugs acting at RXFP1 have potential for the treatment of diseases involving tissue fibrosis such as cardiac and renal failure, asthma and scleroderma and may also be useful to facilitate embryo implantation. Activators of RXFP2 may be useful to treat cryptorchidism and infertility and inhibitors have potential as contraceptives. Studies of the distribution and function of RXFP3 suggest that it is a potential target for anti-anxiety and anti-obesity drugs.
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PMID:Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. 1729 90

The relaxin family peptides have distinct expression profiles and physiological functions. Several of them are the cognate ligands for 4 G-protein-coupled relaxin family peptide receptors (RXFPs; formerly LGR7, LGR8, GPCR135, GPCR142). The relaxin/RXFP1 system has roles in reproductive physiology but is also involved in fibrosis, wound healing and responses to infarction. Relaxin has a potential use in congestive heart failure where fibrosis plays an important role in organ failure. The INSL3/RXFP2 system has biological roles in reproductive biology that may have limited therapeutic potential. However, the recently characterized relaxin-3/RXFP3 system is important in stress/anxiety and body composition. RXFP3 receptor antagonists are potentially novel anti-anxiety and anti-obesity drugs.
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PMID:Relaxin family peptide receptors--from orphans to therapeutic targets. 1867 59

Replacement of disulfide bonds with non-reducible isosteres can be a useful means of increasing the in vivo stability of a protein. We describe the replacement of the A-chain intramolecular disulfide bond of human relaxin-3 (H3 relaxin, INSL7), an insulin-like peptide that has potential applications in the treatment of stress and obesity, with the physiologically stable dicarba bond. Solid phase peptide synthesis was used to prepare an A-chain analogue in which the two cysteine residues that form the intramolecular bond were replaced with allylglycine. On-resin microwave-mediated ring closing metathesis was then employed to generate the dicarba bridge. Subsequent cleavage of the peptide from the solid support, purification of two isomers and their combination with the B-chain via two intermolecular disulfide bonds, then furnished two isomers of dicarba-H3 relaxin. These were characterized by CD spectroscopy, which suggested a structural similarity to the native peptide. Additional analysis by solution NMR spectroscopy also identified the likely cis/trans form of the analogs. Both peptides demonstrated binding affinities that were equivalent to native H3 relaxin on RXFP1 and RXFP3 expressing cells. However, although the cAMP activity of the analogs on RXFP3 expressing cells was similar to the native peptide, the potency on RXFP1 expressing cells was slightly lower. The data confirmed the use of a dicarba bond as a useful isosteric replacement of the disulfide bond.
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PMID:Solid phase synthesis and structural analysis of novel A-chain dicarba analogs of human relaxin-3 (INSL7) that exhibit full biological activity. 1934 40

Research on the neuropeptide relaxin-3 has predominately been conducted in rats. Anatomical studies have yielded important information on the distribution of relaxin-3 and its cognate receptor (RXFP3) within the brain, while functional studies have implicated relaxin-3 as a modulator of feeding and stress responses. Therefore, the relaxin-3/RXFP3 system represents a potential target for novel drugs to treat human disorders such as obesity, anxiety, and depression, but more research into this interesting neuropeptide in different experimental species is still required. Before conducting detailed neurochemical and behavioral examinations of a recently generated relaxin-3 knockout mouse strain, the present study determined whether this mouse was a viable model of relaxin-3 deficiency.
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PMID:Verification of a relaxin-3 knockout/LacZ reporter mouse as a model of relaxin-3 deficiency. 1941 99

People with schizophrenia have an increased risk of metabolic syndrome, with consequent elevated morbidity and mortality, largely due to cardiovascular disease. Metabolic disorders comprise obesity, dyslipidemia and elevated levels of triglycerides, hypertension, and disturbed insulin and glucose metabolism. The elevated risk of metabolic syndrome in individuals suffering from schizophrenia is believed to be multifactorial, related to a genetic predisposition, lifestyle characteristics and treatment with antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7) is a recently identified member of the insulin/relaxin superfamily that plays a role in the regulation of appetite and body weight control. RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like family peptide receptor 3, RXFP3) and relaxin receptor 2 (relaxin/insulin-like family peptide receptor 4, RXFP4). We have investigated the role of ten polymorphisms in these genes (RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2 rs11264422, rs1018730 and rs12124383) in the occurrence of metabolic syndrome phenotypes (obesity, diabetes, hypercholesterolemia, hypertrigyceridemia, and hypertension) in a cross-sectional cohort of 419 US Caucasian patients treated with antipsychotic drugs. We found several associations between relaxin polymorphisms and hypecholesterolemia, obesity and diabetes, suggesting a role for the relaxin/insulin pathway in the development of metabolic disturbance observed in patients treated with antipsychotics.
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PMID:Relaxin polymorphisms associated with metabolic disturbance in patients treated with antipsychotics. 2169 53

Relaxin mediates renal and mesenteric vascular adaptations to pregnancy by increasing endothelium-dependent vasodilation and compliance and decreasing myogenic reactivity. Diet-induced overweight and obesity are associated with impaired endothelial dysfunction and vascular remodeling leading to a reduction in arterial diameter. In this study, we tested the hypothesis that local vascular responses to relaxin are impaired in diet-induced overweight female rats on a high-fat cafeteria-style diet for 9 wk. Rats were chronically infused with either relaxin or placebo for 5 days, and vascular responses were measured in isolated mesenteric arteries and the perfused kidney. Diet-induced overweight significantly increased sensitivity to phenylephrine (by 17%) and vessel wall thickness, and reduced renal perfusion flow (RPFF; by 16%), but did not affect flow-mediated vasodilation, myogenic reactivity, and vascular compliance. In the normal weight rats, relaxin treatment significantly enhanced flow-mediated vasodilation (2.67-fold), decreased myogenic reactivity, and reduced sensitivity to phenylephrine (by 28%), but had no effect on compliance or RPFF. NO blockade by l-NAME diminished most relaxin-mediated effects. In diet-induced overweight rats, the vasodilator effects of relaxin were markedly reduced for flow-mediated vasodilation, sensitivity to phenylephrine, and myogenic response compared with the normal diet rats, mostly persistent under l-NAME. Our data demonstrate that some of the vasodilator responses to in vivo relaxin administration are impaired in isolated mesenteric arteries and the perfused kidney in diet-induced overweight female rats. This does not result from a decrease in Rxfp1 (relaxin family peptide receptor) expression but is likely to result from downstream disruption to endothelial-dependent mechanisms in diet-induced overweight animals.
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PMID:Impaired vascular responses to relaxin in diet-induced overweight female rats. 2217 1

This paper provides a review of the effects of relaxin-3 and structurally related analogues on food intake and related behaviours, in relation to hypothalamic neural networks and chemical messengers known to control feeding, metabolism and body weight, including other neuropeptides and hormones. Soon after relaxin-3 was discovered, pharmacological studies identified the ability of the native peptide to stimulate feeding acutely in adult rats. Although interpretation of these data was confounded by ligand cross-reactivity at relaxin-family peptide (RXFP) receptors, studies with relaxin-3 analogues selective for the native relaxin-3 receptor, RXFP3, confirmed that acute and chronic activation of RXFP3 increased feeding and weight gain, and produced changes in plasma leptin and insulin. These studies also identified the hypothalamus as a locus of action. Studies are now required to identify RXFP3-positive neuron populations involved in the effects of relaxin-3/RXFP3 signalling on metabolic and neuroendocrine homeostasis, and to determine whether peptide-based, nonpeptide-based or gene-based RXFP3 treatments can alter food intake and body weight in animal models of obesity and eating disorders, as a reflection of the therapeutic potential of this newly identified transmitter system.
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PMID:Increased feeding and body weight gain in rats after acute and chronic activation of RXFP3 by relaxin-3 and receptor-selective peptides: functional and therapeutic implications. 2285 7

The insulin-like peptide, relaxin-3 was first identified just a decade ago via a genomic database search and is now recognized to be a key neuropeptide with several roles including the regulation of arousal, stress responses and neuroendocrine homeostasis. It also has significant potential as a drug to treat stress and obesity. Its actions are mediated via its cognate G protein-coupled receptor, RXFP3, which is found in abundant numbers in the brain. However, much remains to be determined with respect to the mechanism of neurological action of this peptide. Consequently, the chemical synthesis of the rat and mouse (which share identical primary structures) two-chain, three disulfide peptide was undertaken and the resulting peptide subjected to detailed in vitro and in vivo assay. Use of efficient solid-phase synthesis methods provided the two regioselectively S-protected A- and B-chains which were readily combined via sequential disulfide bond formation. The synthetic rat/mouse relaxin-3 was obtained in high purity and good overall yield. It demonstrated potent orexigenic activity in rats in that central intracerebroventricular infusion led to significantly increased food intake and water drinking.
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PMID:Chemical synthesis and orexigenic activity of rat/mouse relaxin-3. 2345 88


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